Thioridazine aggravates skeletal myositis, systemic and liver inflammation in Trypanosoma cruzi-infected and benznidazole-treated mice
| Autor: | Reggiani Vilela Gonçalves, Rômulo Dias Novaes, Andréa A.S. Mendonça, Elda Gonçalves-Santos, Kelly J. González-Lozano, Lívia de Figueiredo Diniz, Ivo Santana Caldas, Thaiany G. Souza-Silva |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Chagas disease Trypanosoma cruzi Immunology Inflammation Parasitemia Pharmacology Systemic inflammation Parasite Load Hepatitis Mice 03 medical and health sciences 0302 clinical medicine Acetylglucosaminidase Animals Immunology and Allergy Medicine Chagas Disease NADH NADPH Oxidoreductases Muscle Skeletal Transaminases Myositis Peroxidase biology Thioridazine business.industry technology industry and agriculture medicine.disease biology.organism_classification Trypanocidal Agents Disease Models Animal Drug Combinations 030104 developmental biology Nitroimidazoles Benznidazole 030220 oncology & carcinogenesis Cytokines Female medicine.symptom business Glycogen medicine.drug |
| Zdroj: | International Immunopharmacology. 85:106611 |
| ISSN: | 1567-5769 |
| Popis: | While thioridazine (Tio) inhibits the antioxidant defenses of Trypanosoma cruzi, the gold standard antitrypanosomal drug benznidazole (Bz) has potent anti-inflammatory and pro-oxidant properties. The combination of these drugs has never been tested to determine the effect on T. cruzi infection. Thus, we compared the impact of Tio and Bz, administered alone and in combination, on the development of skeletal myositis and liver inflammation in T. cruzi-infected mice. Swiss mice were randomized into six groups: uninfected untreated, infected untreated, treated with Tio (80 mg/kg) alone, Bz (50 or 100 mg/kg) alone, or a combination of Tio and Bz. Infected animals were inoculated with a virulent T. cruzi strain (Y) and treated by gavage for 20 days. Mice untreated or treated with Tio alone developed the most intense parasitemia, highest parasitic load, elevated IL-10, IL-17, IFN-γ, and TNF-α plasma levels, increased N-acetylglucosaminidase and myeloperoxidase activity in the liver and skeletal muscle, as well as severe myositis and liver inflammation (P < 0.05). All parameters were markedly attenuated in animals receiving Bz alone (P < 0.05). However, the co-administration of Tio impaired the response to Bz chemotherapy, causing a decrease in parasitological control (parasitemia and parasite load), skeletal muscle and liver inflammation, and increased microstructural damage, when compared to the group receiving Bz alone (P < 0.05). Altogether, our findings indicated that Tio aggravates systemic inflammation, skeletal myositis and hepatic inflammatory damage in T. cruzi-infected mice. By antagonizing the antiparasitic potential of Bz, Tio limits the anti-inflammatory, myoprotectant and hepatoprotective effects of the reference chemotherapy, aggravating the pathological remodeling of both organs. As the interaction of T. cruzi infection, Bz and Tio is potentially toxic to the liver, inducing inflammation and microvesicular steatosis; this drug combination represents a worrying pharmacological risk factor in Chagas disease. |
| Databáze: | OpenAIRE |
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